Accession Number ADA566407
Title Oncogenicity and Selective Inhibition of ERG Splicing Variants in Prostate Cancer.
Publication Date Mar 2012
Media Count 34p
Personal Author F. Zammarchi G. Boutsalis G. Rocco L. Cartegni
Abstract ERG, a member of the ETS transcription factor family, is frequently overexpressed in prostate cancer as a result of its fusion to the androgenresponsive Tmprss2 gene. Different genomic rearrangements and alternative splicing events around the junction region lead to multiple combination of Tmprss2:ERG fusion transcripts that correlate with different tumor aggressiveness, but their specific functions and biological activities are still unclear. The complexity of ERG expression pattern is compounded by the use of alternative promoters, splice sites, polyadenylation sites and translation initiation sites in both the native and fusion contexts. Our systematic characterization of native ERG and Tmprss2:ERG variants reveals that their different oncogenic potential is impacted by the status of the Ets domain and the configuration of the 5 UTR region. In particular, expression and activity of functional ERG and Tmprss2:ERG variants are influenced both by translation initiation signals within the different isoforms and by inhibitory upstream Open Reading Frames (uORF) in their 5 UTRs. Stable expression of ERG and Tmprss2:ERG variants promoted cell migration/invasion, induced a block of proliferation and induced a senescence-like state, suggesting a role for these variants in the prostate tumorigenesis process. In addition to Tmprss2:ERG fusion products, a group of related native ERG isoforms is also highly over- expressed in fusioncarrying prostate cancers, and share the same translation initiation site (in ERG exon 4) with the commonly observed Tmprss2 exon1 joined to ERG exon 4 (T1:E4) fusion-derived variant. Usage of this ATG can be preferentially down-regulated by directed antisense-based compounds, possibly representing the basis of a targeted approach that distinguishes between tumor associated and normal ERG.
Keywords Androgens
Chromosomes
Epithelium
Erg(Ets related genes)
Genes
Genetic mapping
Growth(Physiology)
Junctions
Neoplasms
Oncogenic viruses
Patterns
Prostate cancer
Splices
Tmprss2 gene


 
Source Agency Non Paid ADAS
NTIS Subject Category 57F - Cytology, Genetics, & Molecular Biology
57E - Clinical Medicine
Corporate Author Memorial Sloan-Kettering Cancer Center, New York.
Document Type Technical report
Title Note Final rept. 1 Sep 2009-29 Feb 2012.
NTIS Issue Number 1307
Contract Number W81XWH-09-1-0546

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